SV40

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Simian virus 40
Symian virus.png
Virus classification e
(unranked): Virus
Realm: Monodnaviria
Kingdom: Shotokuvirae
Phylum: Cossaviricota
Class: Papovaviricetes
Order: Sepolyvirales
Family: Polyomaviridae
Genus: Betapolyomavirus
Species:
Virus:
Simian virus 40

SV40 is an abbreviation for simian vacuolating virus 40 or simian virus 40, a polyomavirus that is found in both monkeys and humans. Like other polyomaviruses, SV40 is a DNA virus that sometimes causes tumors in animals, but most often persists as a latent infection. SV40 has been widely studied as a model eukaryotic virus, leading to many early discoveries in eukaryotic DNA replication[1] and transcription.[2]

Following contamination of polio vaccine batches in the 1950s and 1960s, SV40 came under suspicion as a possible cancer risk, but no subsequent increased cancer rate was observed, making such a risk unlikely. Nevertheless SV40 has become a cause célèbre for anti-vaccination activists, who have blamed it for multiple ills, including cancer and HIV/AIDS.[3]

Virology

SV40 consists of an unenveloped icosahedral virion with a closed circular double-stranded DNA genome[4] of 5.2 kb.[5] The virion adheres to cell surface receptors of MHC class I by the virion glycoprotein VP1. Penetration into the cell is through a caveolin vesicle. Inside the cell nucleus, the cellular RNA polymerase II acts to promote early gene expression. This results in an mRNA that is spliced into two segments. The small and large T antigens result from this. The large T antigen has two functions: 5% goes to the plasma cell membrane and 95% returns to the nucleus. Once in the nucleus the large T antigen binds three viral DNA sites, I, II and III. Binding of sites I and II autoregulates early RNA synthesis. Binding to site II takes place in each cell cycle. Binding site I initiates DNA replication at the origin of replication. Early transcription gives two spliced RNAs that are both 19s. Late transcription gives both a longer 16s, which synthesizes the major viral capsid protein VP1; and the smaller 19s, which gives VP2 and VP3 through leaky scanning. All of the proteins, besides the 5% of large T, return to the nucleus because assembly of the viral particle happens there. A putative late protein VP4 has been reported to act as a viroporin facilitiating release of viral particles and resulting in cytolysis;[6][7] however the presence and role of VP4 have been disputed.[8][9]

Multiplicity reactivation

SV40 is capable of multiplicity reactivation (MR).[10][11] MR is the process by which two or more virus genomes containing otherwise lethal damage interact within an infected cell to form a viable virus genome. Yamamato and Shimojo observed MR when SV40 virions were irradiated with UV light and allowed to undergo multiple infection of host cells.[10] Hall studied MR when SV 40 virions were exposed to the DNA crosslinking agent 4, 5', 8-trimethylpsoralen.[11] Under conditions in which only a single virus particle entered each host cell, approximately one DNA cross-link was lethal to the virus and could not be repaired. In contrast, when multiple viral genomes infected a host cell, psoralen-induced DNA cross-links were repaired; that is, MR occurred. Hall suggested that the virions with cross-linked DNA were repaired by recombinational repair.[11] Michod et al. reviewed numerous examples of MR in different viruses and suggested that MR is a common form of sexual interaction that provides the advantage of recombinational repair of genome damages.[12]

Transcription

The early promoter for SV40 contains three elements. The TATA box is located approximately 20 base-pairs upstream from the transcriptional start site. The 21 base-pair repeats contain six GC boxes and are the site that determines the direction of transcription. Also, the 72 base-pair repeats are transcriptional enhancers. When the SP1 protein interacts with the 21 base-pair repeats, it binds either the first or the last three GC boxes. Binding the first three initiates early expression, binding the last three initiates late expression. The function of the 72 base-pair repeats is to enhance the amount of stable RNA and increase the rate of synthesis. This is done by binding (dimerization) with the AP-1 transcription factor to give a primary transcript that is 3' polyadenylated and 5' capped.[citation needed]

Human disease

Transmission electron micrograph of polyomavirus SV40

The hypothesis that SV40 might cause cancer in humans was a particularly controversial area of research, fuelled by the historical contamination of some batches of polio vaccine with SV40 in the 1950s and 1960s.[13] "Persuasive evidence now indicates that SV40 is causing infections in humans today and represents an emerging pathogen."[14]However "It appears unlikely that SV40 infection alone is sufficient to cause human malignancy..."[15]

p53 damage and carcinogenicity

It has been suggested that SV40 may act as a co-carcinogen with crocidolite asbestos to cause mesothelioma.[16][17]

Polio vaccine contamination

Some vaccines made in the US between 1955 and 1961 were found to be contaminated with SV40, from the growth medium and from the original seed strain. Population level studies did not show extensive evidence of increase in cancer incidence as a result of exposure,[18] though SV40 has been extensively studied.[19] A thirty-five year follow-up did not find excess numbers of cancers associated with SV40.[20]

Other animals

SV40 is dormant and is asymptomatic in rhesus monkeys. The virus has been found in many macaque populations in the wild, where it rarely causes disease. However, in monkeys that are immunodeficient—due to, for example, infection with simian immunodeficiency virus—SV40 acts much like the human JC and BK polyomaviruses, producing kidney disease and sometimes a demyelinating disease similar to progressive multifocal leukoencephalopathy. In other species, particularly hamsters, SV40 causes a variety of tumors, generally sarcomas. In rats, the oncogenic SV40 large T antigen was used to establish a brain tumor model for primitive neuroectodermal tumor and medulloblastoma.[21]

The molecular mechanisms by which the virus reproduces and alters cell function were previously unknown, and research into SV40 vastly increased biologists' understanding of gene expression and the regulation of cell growth.[citation needed]

Gene therapy

Due to its high tissue tropism, biotechnology companies seek to utilize modified SV40 based vectors as a viral vector for gene therapy. In these helper dependent virus or packaging cell line assisted produced vectors the SV40 large T antigen and SV40 small T antigen are removed.[22][23][24]

History

SV40 was first identified by Ben Sweet and Maurice Hilleman in 1960 when they found that between 10 and 30% of polio vaccines in the US were contaminated with SV40.[25] In 1962, Bernice Eddy described the SV40 oncogenic function inducing sarcoma and ependymomas in hamsters inoculated with monkeys cells infected with SV40.[26] The complete viral genome was sequenced by Weissman at Yale University (US)[27] in 1978 and also by Fiers and his team at the University of Ghent (Belgium).[28]

Culture and society

SV40 has become a totemic subject among anti-vaccination activists, where its presence in contaminated vaccine is accused of being a cause of a cancer "epidemic" and of being responsible for HIV/AIDS.[3]

See also

References

  1. Fanning, E; Zhao, K (February 2009). "SV40 DNA replication: From the A gene to a nanomachine". Virology. 384 (2): 352–359. doi:10.1016/j.virol.2008.11.038. PMC 2718763. PMID 19101707.
  2. Banerji, J; Rusconi, S; Schaffner, W (December 1981). "Expression of a β-globin gene is enhanced by remote SV40 DNA sequences". Cell. 27 (2): 299–308. doi:10.1016/0092-8674(81)90413-X. PMID 6277502. S2CID 54234674.
  3. 3.0 3.1 Gorski DH (9 September 2013). "Another antivaccine zombie meme: polio vaccine and SV40 and cancer, oh, my!". Science-Based Medicine. Archived from the original on 14 November 2023. Retrieved 13 December 2023.
  4. Fanning, E; Zhao, K (2009). "SV40 DNA replication: from the A gene to a nanomachine". Virology. 384 (2): 352–359. doi:10.1016/j.virol.2008.11.038. PMC 2718763. PMID 19101707.
  5. Sowd, GA; Fanning, E (2012). "A wolf in sheep's clothing: SV40 co-opts host genome maintenance proteins to replicate viral DNA". PLOS Pathogens. 8 (11): e1002994. doi:10.1371/journal.ppat.1002994. PMC 3493471. PMID 23144614.
  6. Raghava, Smita; Giorda, Kristina M.; Romano, Fabian B.; Heuck, Alejandro P.; Hebert, Daniel N. (30 June 2011). "The SV40 Late Protein VP4 Is a Viroporin that Forms Pores to Disrupt Membranes for Viral Release". PLOS Pathogens. 7 (6): e1002116. doi:10.1371/journal.ppat.1002116. PMC 3128117. PMID 21738474.
  7. DeCaprio, James A.; Garcea, Robert L. (April 2013). "A cornucopia of human polyomaviruses". Nature Reviews Microbiology. 11 (4): 264–276. doi:10.1038/nrmicro2992. PMC 3928796. PMID 23474680.
  8. Henriksen, Stian; Rinaldo, Christine Hanssen (29 April 2020). "Does the Evidence Support the Existence of the Simian Polyomavirus SV40 Vp4 Viroporin?". mSphere. 5 (2): e00019-20. doi:10.1128/mSphere.00019-20. PMC 7082134. PMID 32188744.
  9. Daniels, Robert; Hebert, Daniel N. (29 April 2020). "In Support of Simian Polyomavirus 40 VP4 as a Later Expressed Viroporin". mSphere. 5 (2): e00187-20. doi:10.1128/mSphere.00187-20. PMC 7082142. PMID 32188752.
  10. 10.0 10.1 Yamamoto, Hiroshi; Shimojo, H (August 1971). "Multiplicity reactivation of human adenovirus type 12 and simian virus 40 irradiated by ultraviolet light". Virology. 45 (2): 529–31. doi:10.1016/0042-6822(71)90355-2. PMID 4328814.
  11. 11.0 11.1 11.2 Hall, J. D. (1982). "Repair of psoralen-induced crosslinks in cells multiply infected with SV40". Molecular & General Genetics. 188 (1): 135–8. doi:10.1007/bf00333007. PMID 6294477. S2CID 5843939.
  12. Michod, Richard E.; Bernstein, Harris; Nedelcu, Aurora M. (2008). "Adaptive value of sex in microbial pathogens". Infection, Genetics and Evolution. 8 (3): 267–85. doi:10.1016/j.meegid.2008.01.002. PMID 18295550.
  13. Poulin, D. L.; Decaprio, J. A. (2006). "Is There a Role for SV40 in Human Cancer?". Journal of Clinical Oncology. 24 (26): 4356–65. doi:10.1200/JCO.2005.03.7101. PMID 16963733.
  14. Vilchez, Regis A.; Butel, Janet S. (July 2004). "Emergent Human Pathogen Simian Virus 40 and Its Role in Cancer". Clinical Microbiology Reviews. 17 (3): 495–508. doi:10.1128/CMR.17.3.495-508.2004. ISSN 0893-8512. PMID 15258090. S2CID 10372679. Archived from the original on 9 December 2023. Retrieved 13 December 2023.
  15. Qi F, Carbone M, Yang H, Gaudino G (October 2011). "Simian virus 40 transformation, malignant mesothelioma and brain tumors". Expert Rev Respir Med (Review). 5 (5): 683–97. doi:10.1586/ers.11.51. PMC 3241931. PMID 21955238.
  16. Kroczynska, Barbara; Cutrone, Rochelle; Bocchetta, Maurizio; Yang, Haining; Elmishad, Amira G.; Vacek, Pamela; Ramos-Nino, Maria; Mossman, Brooke T.; Pass, Harvey I.; Carbone, Michele (19 September 2006). "Crocidolite asbestos and SV40 are cocarcinogens in human mesothelial cells and in causing mesothelioma in hamsters". Proceedings of the National Academy of Sciences. 103 (38): 14128–14133. Bibcode:2006PNAS..10314128K. doi:10.1073/pnas.0604544103. PMC 1599923. PMID 16966607.
  17. Pershouse, Mark A.; Heivly, Shane; Girtsman, Teri (January 2006). "The Role of SV40 in Malignant Mesothelioma and Other Human Malignancies". Inhalation Toxicology. 18 (12): 995–1000. doi:10.1080/08958370600835377. PMID 16920674. S2CID 30590705.
  18. "Studies Find No Evidence That Simian Virus 40 Is Related To Human Cancer". Science Daily (Press release). NIH/National Cancer Institute. 25 August 2004. Archived from the original on 30 December 2022. Retrieved 13 December 2023.
  19. Hilleman MR (1998). "Discovery of simian virus 40 (SV40) and its relationship to poliomyelitis virus vaccines". Dev Biol Stand. 94: 183–90. PMID 9776239.
  20. Carroll-Pankhurst, C; Engels, EA; Strickler, HD; Goedert, JJ; Wagner, J; Mortimer EA Jr. (November 2001). "Thirty-five year mortality following receipt of SV40- contaminated polio vaccine during the neonatal period". Br J Cancer. 85 (9): 1295–7. doi:10.1054/bjoc.2001.2065. PMC 2375249. PMID 11720463.
  21. Eibl, R. H.; Kleihues, P; Jat, P. S.; Wiestler, O. D. (1994). "A model for primitive neuroectodermal tumors in transgenic neural transplants harboring the SV40 large T antigen". The American Journal of Pathology. 144 (3): 556–64. PMC 1887088. PMID 8129041.
  22. Mueller, C.; Strayer, M. S.; Sirninger, J.; Braag, S.; Branco, F.; Louboutin, J.-P.; Flotte, T. R.; Strayer, D. S. (February 2010). "In vitro and in vivo functional characterization of gutless recombinant SV40-derived CFTR vectors". Gene Therapy. 17 (2): 227–237. doi:10.1038/gt.2009.137. PMC 2820588. PMID 19890354.
  23. Toscano, Miguel G.; van der Velden, Jeroen; van der Werf, Sybrand; Odijk, Machteld; Roque, Ana; Camacho-Garcia, Rafael J.; Herrera-Gomez, Irene G.; Mancini, Irene; de Haan, Peter (15 September 2017). "Generation of a Vero-Based Packaging Cell Line to Produce SV40 Gene Delivery Vectors for Use in Clinical Gene Therapy Studies". Molecular Therapy. Methods & Clinical Development. 6: 124–134. doi:10.1016/j.omtm.2017.06.007. PMC 5537168. PMID 28791314.
  24. Vera, Maria; Fortes, Puri (May 2004). "Simian Virus-40 as a Gene Therapy Vector". DNA and Cell Biology. 23 (5): 271–282. doi:10.1089/104454904323090903. PMID 15169607.
  25. Sweet, B. H.; Hilleman, M. R. (November 1960). "The vacuolating virus, S.V. 40". Proceedings of the Society for Experimental Biology and Medicine. 105 (2): 420–427. doi:10.3181/00379727-105-26128. PMID 13774265. S2CID 38744505.
  26. Eddy, B. E.; Borman, G. S.; Grubbs, G. E.; Young, R. D. (May 1962). "Identification of the oncogenic substance in rhesus monkey kidney cell culture as simian virus 40". Virology. 17: 65–75. doi:10.1016/0042-6822(62)90082-x. PMID 13889129.
  27. Reddy, V. B.; Weissman, S. M. (May 1978). "The genome of simian virus 40". Science. 200 (4341): 494–502. Bibcode:1978Sci...200..494R. doi:10.1126/science.205947. PMID 205947.
  28. Fiers, W; Contreras, R; Haegemann, G; Rogiers, R; Van De Voorde, A; Van Heuverswyn, H; Van Herreweghe, J; Volckaert, G; Ysebaert, M (May 1978). "Complete nucleotide sequence of SV40 DNA". Nature. 273 (5658): 113–20. Bibcode:1978Natur.273..113F. doi:10.1038/273113a0. PMID 205802. S2CID 1634424.

External links

Classification


CDC FAQ

  • "Simian Virus 40 (SV40) - 1955 – 1963" in "Historical Safety Concerns". Vaccine Safety. CDC. 30 March 2022. Archived from the original on 18 December 2023. Retrieved 13 December 2023.

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